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Exposure to anticancer drugs can result in transgenerational genomic instability in mice.

The genetic effects of human exposure to anticancer drugs remain poorly understood. To establish whether exposure to anticancer drugs can result not only in mutation induction in the germ line of treated animals, but also in altered mutation rates in their offspring, we evaluated mutation rates in t... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America February 21, 2012, Vol.109(8), pp.2984-2988
Main Author: Glen, Colin D
Other Authors: Dubrova, Yuri E
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 1091-6490 ; DOI: 10.1073/pnas.1119396109
Link: http://search.proquest.com/docview/923192114/?pq-origsite=primo
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title: Exposure to anticancer drugs can result in transgenerational genomic instability in mice.
format: Article
creator:
  • Glen, Colin D
  • Dubrova, Yuri E
subjects:
  • Animals–Adverse Effects
  • Antineoplastic Agents–Drug Effects
  • Female–Genetics
  • Genetic Loci–Drug Effects
  • Genomic Instability–Genetics
  • Germ-Line Mutation–Drug Effects
  • Heredity–Genetics
  • Male–Drug Effects
  • Mice–Genetics
  • Mice, Inbred Balb C–Drug Effects
  • Mutation Rate–Genetics
  • Pedigree–Genetics
  • Tandem Repeat Sequences–Genetics
  • Antineoplastic Agents
ispartof: Proceedings of the National Academy of Sciences of the United States of America, February 21, 2012, Vol.109(8), pp.2984-2988
description: The genetic effects of human exposure to anticancer drugs remain poorly understood. To establish whether exposure to anticancer drugs can result not only in mutation induction in the germ line of treated animals, but also in altered mutation rates in their offspring, we evaluated mutation rates in the offspring of male mice treated with three commonly used chemotherapeutic agents: cyclophosphamide, mitomycin C, and procarbazine. The doses of paternal exposure were approximately equivalent to those used clinically. Using single-molecule PCR, the frequency of mutation at the mouse expanded simple tandem repeat locus Ms6-hm was established in DNA samples extracted from sperm and bone marrow of the offspring of treated males. After paternal exposure to any one of these three drugs, expanded simple tandem repeat mutation frequencies were significantly elevated in the germ line (sperm) and bone marrow of their offspring. This observed transgenerational instability was attributed to elevated mutation rates at the alleles derived from both the exposed fathers and from the nonexposed mothers, thus implying a genome-wide destabilization. Our results suggest that paternal exposure to a wide variety of mutagens can result in transgenerational instability manifesting in their offspring. Our data also raise important issues concerning delayed transgenerational effects in the children of survivors of anticancer therapy. epigenetic | genetic risk doi/10.1073/pnas.1119396109
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 1091-6490 ; DOI: 10.1073/pnas.1119396109
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleExposure to anticancer drugs can result in transgenerational genomic instability in mice.
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descriptionThe genetic effects of human exposure to anticancer drugs remain poorly understood. To establish whether exposure to anticancer drugs can result not only in mutation induction in the germ line of treated animals, but also in altered mutation rates in their offspring, we evaluated mutation rates in the offspring of male mice treated with three commonly used chemotherapeutic agents: cyclophosphamide, mitomycin C, and procarbazine. The doses of paternal exposure were approximately equivalent to those used clinically. Using single-molecule PCR, the frequency of mutation at the mouse expanded simple tandem repeat locus Ms6-hm was established in DNA samples extracted from sperm and bone marrow of the offspring of treated males. After paternal exposure to any one of these three drugs, expanded simple tandem repeat mutation frequencies were significantly elevated in the germ line (sperm) and bone marrow of their offspring. This observed transgenerational instability was attributed to elevated mutation rates at the alleles derived from both the exposed fathers and from the nonexposed mothers, thus implying a genome-wide destabilization. Our results suggest that paternal exposure to a wide variety of mutagens can result in transgenerational instability manifesting in their offspring. Our data also raise important issues concerning delayed transgenerational effects in the children of survivors of anticancer therapy. epigenetic | genetic risk doi/10.1073/pnas.1119396109
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